This invention relates to 6 Chloro-7,8-dihydroxy-1-(4'-hydroxyphenyl) 2,3,4,5-tetrahydro-1 H-3-benzazepine carbamates as prodrugs and their use as antihypertensive agents.
Prodrugs are biologically reversible derivatives which revert back to the parent molecule by virtue of enzymatic and/or chemical lability. They utilize a chemical molecule of proven biological activity (parent molecule) and deliver it to the site of action while overcoming some inherent drawback to the use of the parent compound. Prodrugs are chemical modifications which result in improved pharmaceutical, physiochemical and pharmacalogical properties and yet retain their desired biological activity.
Certain 6 halo-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3, 4,5-tetrahydro-1H-3-benzazepines are described in U.S. Pat. No. 4,197,297 to have antihypertensive activity by means of their peripheral dopaminergic effect. The leading species described there is the 6-chloro-congener known as fenoldopam. A limiting factor for the clinical use of fenoldopam orally is its low bioavailability due to its high first pass metabolism. This results in an initial high peak plasma level. The half life associated with fenoldopam is reportedly short and frequent dosing is necessary to sustain effective plasma concentrations with an oral dosing regimen.
It has been unexpectedly discovered that certain the carbomate derivatives of fenoldopam were administered to dogs they provided therapeutic plasma levels of the compound over a much longer period of time than the parent ccmpound itself. An absence of a high initial peak effect associated with the parent compound was also noted. The fenoldopam carbanates of this invention have the following structural formula: ##STR1## in which R.sub.6 is halo and R.sub.7, R.sub.8 and R.sub.4, are each independently hydrogen or CONHR where in R is a lower alkyl having from one to four carbon atoms. Preferably R.sub.7, and R.sub.8 are COHC.sub.2 H.sub.5 and R.sub.4, is hydrogen. Another advantageous compound of this invention is the trisethyl carbamate having the basic structural formula: ##STR2##
The pharmaceutically acceptable acid addition salts having the utility of the free bases of Formula I are part of this invention. They are prepared by methods well known to the art and are formed with both inorganic or organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedi-sulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, methanesulfonic, cyclohexysulfamic, phosphoric and nitric acids. The hydrohalic and especially methanesulfonic acid salts are of particular utility. Similarly the quarternary salts include those prepared from organic halides such as methyl iodide, ethyl iodide, benzyl chloride and the like.
It will be obvious to one skilled in the art that the compounds of Formula 1 may be present as diastereoisomers which may be prepared as the individual R or S optical isomers. Resolution of the optical isomers of a convenient methoxy intermediate may be accomplished by fractional crystallization of their salts with optically active acids from appropriate solvents. Specific methods of resolution and preparation of the R-enantiomer of fenoldopam are disclosed in Acta Pharmaceutica Suecica Suppl.2, 1983, pages 132-150. Unless otherwise specified herein or in the claims, it is intended to include all isomers, whether separated or mixtures thereof. Where isomers are separated, the desired pharmacological activity will usually predominate in one of the isomers. Preferably, the R enantiomer is used for the purposes of this invention.
The methods of using the new compounds of this invention for medical purposes manifest themselves in a number of ways. Broadly speaking a peripheral dopaminergic effect is induced in patients in need thereof. The compounds, for example, cause vasodilation of dopaminergically innervated blood vessels. The result is to induce an increased renal blood flow. The end result will be an antihypertensive effect on patients having elevated blood pressures or to maintain stabilized blood pressures in patients prone to elevated pressures. This assertion does not rule out that the end result may be partially due to another mechanism of action. Other clinical uses for fenoldopam are in the treatment of congestive heart failure and renal failure, and the new compounds will provide more prolonged therapy.
The renal blood flow of the compounds of Formula 1 was readily measured in female mongrel dogs which underwent chronic implantation of a renal flow probe and arterial Vascular-Acess-Port. Briefly, the dogs were anesthetizied and using standard asceptic techniques, a Transonic flow probe was placed around the left renal artery and the connector tunneled subcutaneously to the back of the dog. The Vascular-Access-Port was placed in the left femoral artery and the access portion tacked to the underlying muscle in the area of the paralumbar-fossa. The patency of the Vascular Access Port was maintained by weekly flushing of the catheter and locking with a 50% glucose 500 U/ml heparinized solution. Dogs were trained to lie quietly restrained on a board and the connector portion of the flow probe was exteriorized under local anesthesia and connected to a Transonic flowmeter. Renal blood flow was recorded continuously on a Gilson chart recorder. Mean arterial pressure was monitored directly from the Vascular-Access-Port using a 23 gauge butterfly. Mean arterial blood pressure and renal blood flow were recorded before and for 6 hr. after the oral or i.v. administration of the R-enantiomers of the parent compound (fenoldopam) and the prodrug of fenoldopam. At the end of the experiment, the flow probe connector was returned to its subcutaneous position and the skin incision closed with chromic gut and skin staples. The VAP was again flushed and a fresh heparin glucose lock established. Standard sterile procedures followed during the removal and replacement of the flow probe connector.
During the experiment post drug blood samples were withdrawn periodically in order to determine the plasma levels of the parent drug, i.e., fenoldopam plasma levels.
The parent compound R-6-chloro-7,8-dihydroxy-1-(4'-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benz azepine tested orally for renal blood flow in 4 dogs as described above resulted in a significant increase (80%) in renal blood flow. The effect was transient and renal blood flow had returned to control values within 60 minutes. The plasma fenoldopam level in these dogs peaked in 5 minutes and showed a similar transient response as was observed with the renal blood flow.
In contrast, oral administration of the R-enantiomer of Formula 11, resulted in a sustained (4-6 hours) increase in both renal blood flow and plasma fenoldopam.
The sustained increase in renal blood flow and plasma fenoldopam levels were not due to slow oral absorption since intravenous administration of this prodrug also gave similar results.
The half life for plasma fenoldopam after oral administration of fenoldopam and the R-enantioner of Formula II were 12 minutes and 4.6 hours respectively.
The pharmaceutical compositions of this invention having peripheral dopaminergic activity are prepared in conventional dosage unit forms by incorporating a compound of Formula I, an isomer or a pharmaceutically acceptable acid addition salt or derivative thereof, with a nontoxic pharmaceutical carrier according to accepted procedures in a nontoxic amount sufficient to produce the desired pharmacodynamic activity in a subject, animal or human. Preferably the compositions will contain the active ingredient in an active but nontoxic amount selected from about 10 mg to about 1.0 g, preferably about 50-500 mg of the active ingredient per dosage unit. This quanity depends on the relative potency of the basic compound, the specific biological activity desired, the route of administration and the conditions of the patient. The preferred compounds of this invention especially as the hydrochloride salts have been found to have good absorbability from the gastrointestinal tract so oral dosage forms are of prime importance here preferably selected from the dosage unit ranges given above. Intravenous or subcutaneous doses would be lower.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent may include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. Such sustained release products as well as derivatives which may be gradually metabolized to the active parent can be employed to prolong the unique biological activity of the compounds of this invention.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier for oral administration is used the preparation can be tableted, placed in a hard gelatin capsule in powder, regular or sustained release pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampul, or an aqueous or nonaqueous liquid suspension.
The pharmaceutical preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to give the desired end product.
The method of producing dopaminergic activity in accordance with this invention comprises administering internally to a subject in need of such activity a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, usually combined with a pharmaceutical carrier, in a nontoxic amount sufficient to produce said activity as described above. The route of administration may be any route which effectively transports the active compound to the dopamine receptors which are to be stimulated such as orally or parenterally, the oral route being preferred. Advantageously, equal doses within the ranges given above will be administered several times, such as from two to five times, a day with the daily dosage regimen being selected from about 10 mg. to about 1.0 g. preferably 50 mg. to 2.0 g. for oral dosage units. When the method described above is carried out antihypertensive activity is produced. For an average size human for the preferred species (II) a preferred oral dose to show antihypertensive activity would be selected from the range of from about 25 to 500 mg. for each dosage unit adapted for oral administration to be administered from 1-5 times daily.